Treatment of cancer with therapeutic monoclonal antibody specific for a tumor associated antigen and an immune adjuvant

ABSTRACT

The present document describes a method of inhibiting cancer tumor growth in a patient in need thereof, comprising at least a first treatment comprising steps a) and b): a) administering to the patient an immune adjuvant in combination with a therapeutic monoclonal antibody specific for a tumor associated antigen; and b) administering to the patient the immune adjuvant; and a final treatment consisting of administering to the patient the therapeutic monoclonal antibody specific for a tumor associated antigen, wherein time between step a) and step b) is a time sufficient for treatment of the patient with the immune adjuvant, and wherein time between the step b) and the final treatment is from about 10 to about 14 weeks.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation U.S. patent application Ser. No.15/470,733, filed Mar. 27, 2017 which of claims the benefit of priorityto U.S. Provisional Patent Application No. 62/455,114 filed on Feb. 6,2017, the disclosures of which are hereby incorporated by reference intheir entireties.

BACKGROUND (A) Field

The subject matter disclosed generally relates to methods of inhibitingcancer tumor growth in a patient in need thereof. More specifically, thesubject matter disclosed relates to methods of inhibiting cancer tumorgrowth in a patient by administering a first treatment comprisingadministering a therapeutic monoclonal antibody specific for a tumorassociated antigen in combination with an immune adjuvant; and thenadministering to an immune adjuvant, followed by a final treatment withthe therapeutic monoclonal antibody specific for a tumor associatedantigen.

(b) Related Prior Art

Ovarian cancer is the most common cause of gynecologic cancer deaths inthe United States. Cytotoxic therapy produces high initial responserates; however, recent intergroup study involving more than 4000patients was unable to improve progression-free (PFS) or overallsurvival in any of the 4 experimental combinations that added a thirddrug with documented single agent activity to the standard front-linetreatment [Bookman M. GOG0182-ICON5: J Clin Oncol. 2006; 24(18S):256s;Braly et al. (J Immunother 2009; 32:54-65].

It is well established that aberrant expression of membrane mucin MUC16(also known as CA125) is associated with tumor progression andmetastasis of cancers such as ovarian and pancreatic cancer. The role ofMUC16 in tumor progression and metastasis occurs through interactionwith oncogenic modulators. For instance, it is understood that aberrantexpression of MUC16 in ovarian cancer cells facilitates peritonealmetastasis through interactions with mesothelin (tumor differentiationfactor) and through immunosuppressive functions by blocking naturalkiller cell-mediated cytotoxicity, while overexpression of MUC16increases breast cancer cell proliferation via stimulation of Januskinase 2 (JAK2). It is also understood that MUC16 is upregulated inpancreatic cancers, and expression is increased in livermetastases—although expression of MUC16 was not detected in pancreaticintraepithelial neoplasia (PanIN) nor in normal pancreas, suggestingthat expression of MUC16 may occur later in disease progression.

The administration of mono-immunotherapy, in the form of MUC16-specificmurine monoclonal antibody oregovomab (mAb-M43.13) following front-linetherapy with chemotherapy failed to improves clinical outcome inadvanced ovarian cancer (Berek et al. J Clin Onc 27:418-425, 2009).Furthermore a study of chemo-immunotherapy by Braly et al. (J Immunother2009; 32:54-65) showed that simultaneous administration of oregovomabimmunotherapy with the standard carboplatin-paclitaxel chemotherapyresulted in more vigorous immune response to the immunization thanfollowing chemotherapy. However, this study did not comprise a treatmentgroup without oregovomab immunotherapy. Also, this study did not assesswhat the ideal duration of immunization would be for a beneficialtreatment. Therefore, the benefits of combining immunotherapy withchemotherapy remained unclear.

Therefore, there is a need for novel method for use of therapeuticmonoclonal antibodies with immune adjuvants.

SUMMARY

According to an embodiment, there is provided a method of inhibitingcancer tumor growth in a patient in need thereof, comprising:

-   -   at least a first treatment comprising steps a) and b):    -   a) administering to the patient an immune adjuvant in        combination with a therapeutic monoclonal antibody specific for        a tumor associated antigen; and    -   b) administering to the patient the immune adjuvant; and    -   a final treatment consisting of administering to the patient the        therapeutic monoclonal antibody specific for a tumor associated        antigen,        wherein time between step a) and step b) may be a time        sufficient for treatment of the patient with the immune        adjuvant, and wherein time between the step b) and the final        treatment may be from about 10 to about 14 weeks.

The method may further comprise a second treatment comprising step a)and step b), with a time sufficient for treatment of the patient withthe immune adjuvant between the step b) of the first treatment and stepa) of the second treatment.

The method may further comprise a third treatment comprising step a) andstep b), with a time sufficient for treatment of the patient with theimmune adjuvant between the step b) of the second treatment and step a)of the third treatment.

According to another embodiment, there is provided a method ofinhibiting cancer tumor growth in a patient in need thereof, comprising:

-   -   a first, second and third treatment comprising steps a) and b):    -   a) administering to the patient a therapeutic monoclonal        antibody specific for an tumor associated antigen in combination        with an immune adjuvant; and    -   b) administering to the patient the immune adjuvant; and    -   a final treatment consisting of administering to the patient the        therapeutic monoclonal antibody specific for a tumor associated        antigen,        wherein time between step a) and step b) may be from a time        sufficient for treatment of the patient with the immune        adjuvant, wherein time between step b) of the first treatment        and step a) of the second treatment, and step b) of the second        treatment and step a) of the third treatment may be a time        sufficient for treatment of the patient with the immune        adjuvant, and wherein time between the at least one treatment        and the final treatment may be from about 10 to about 14 weeks.

The immune adjuvant may be a chemotherapeutic agent, animmunostimulatory compound, an immune homeostatic checkpoint inhibitor,or a combination thereof.

The therapeutic monoclonal antibody specific for a tumor associatedantigen may be an antibody specific to CA125. The antibody specific toCA125 may be mAb-B43.13 (oregovomab).

The chemotherapeutic agent may be a platinum-based chemotherapy, taxol,doxorubicin, topotecan, a poly (adenosine diphosphate-ribose) polymerase(PARP) inhibitor, or combinations thereof.

The platinum-based chemotherapy comprises cisplatin, carboplatin,oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin,picoplatin, satraplatin, and combinations thereof.

The immunostimulatory compound may be a TLR3 agonist, a TLR4 agonist, orcombinations thereof.

The TLR3 agonist may be polyiC, polyICLC (Hiltonol®).

The chemotherapeutic agent may be a combination of carboplatin andtaxol.

The therapeutic monoclonal antibody specific for a tumor associatedantigen may be mAb-B43.13 (oregovomab), and the chemotherapeutic agentis a combination of carboplatin and taxol.

The immune homeostatic checkpoint inhibitor may be an anti-PDL-1antibody, an anti-CTLA-4 antibody, and anti-PD-1 antibody, orcombinations thereof.

The anti-PDL-1 antibody may be selected from the group consisting ofB7-H1 antibody, BMS-936559 antibody, MPDL3280A (atezolizumab) antibody,MEDI-4736 antibody, MSB0010718C antibody or combinations thereof.

The anti-CTLA-4 antibody may be selected from the group consisting ofipilimumab or tremelimumab or combinations thereof.

The anti-PD-1 antibody may be selected from the group consisting ofNivolumab antibody, pembrolizumab antibody, pidilizumab antibody orcombinations thereof, and AMP-224.

The a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor isselected from the group consisting of olaparib, niraparib, rucaparib,talazoparib, veliparib, CEP 9722, E7016, and BGB-290, or combinationsthereof.

The cancer may be ovarian cancer.

According to another embodiment, there is provided an immune adjuvantand a therapeutic monoclonal antibody specific for a tumor associatedantigen for use in inhibiting tumor cancer growth in a patient, whereinthe immune adjuvant and therapeutic monoclonal antibody specific for atumor associated antigen are administered according to:

-   -   at least one sequential use of (a) followed by (b):    -   (a) the immune adjuvant and the therapeutic monoclonal antibody        specific for a tumor associated antigen, administered together        to the patient;    -   (b) the immune adjuvant, administered to the patient; and    -   a final use consisting of the therapeutic monoclonal antibody        specific for a tumor associated antigen, administered to the        patient,        wherein time between (a) and (b) is a time sufficient for        treatment of the patient with the immune adjuvant, and        wherein time between the (b) and the final use is from about 10        to about 14 weeks.

The immune adjuvant and a therapeutic monoclonal antibody specific for atumor associated antigen may further comprise another (a second)sequential use of (a) followed by (b) according to the presentinvention.

The immune adjuvant and a therapeutic monoclonal antibody specific for atumor associated antigen may further comprise another (a third)sequential use of (a) followed by (b) according to the presentinvention.

The immune adjuvant and a therapeutic monoclonal antibody specific for atumor associated antigen according to the present invention maycomprise:

-   -   a first, second and third sequential use of (a) followed by (b):    -   (a) the immune adjuvant and the therapeutic monoclonal antibody        specific for a tumor associated antigen, administered together        to the patient;    -   (b) the immune adjuvant, administered to the patient; and    -   a final use consisting of the therapeutic monoclonal antibody        specific for a tumor associated antigen administered to the        patient,        wherein time between (a) and (b) is from a time sufficient for        treatment of the patient with the immune adjuvant,        wherein time between (b) of the first sequential use and (a) of        the second sequential use, and (b) of the second sequential use        and (a) of the third sequential use is a time sufficient for        treatment of the patient with the immune adjuvant, and        wherein time between the third sequential use and the final use        is from about 10 to about 14 weeks.

The immune adjuvant may be a chemotherapeutic agent, animmunostimulatory compound, an immune homeostatic checkpoint inhibitor,or a combination thereof.

The therapeutic monoclonal antibody specific for a tumor associatedantigen may be an antibody specific to CA125.

The antibody specific to CA125 may be mAb-B43.13 (oregovomab).

The chemotherapeutic agent may be a platinum-based chemotherapy, taxol,doxorubicin, topotecan, a poly(adenosine diphosphate-ribose) polymerase(PARP) inhibitor, or combinations thereof.

The platinum-based chemotherapy may comprise cisplatin, carboplatin,oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin,picoplatin, satraplatin, and combinations thereof.

The immunostimulatory compound may be a TLR3 agonist, a TLR4 agonist, orcombinations thereof, preferably, the TLR3 agonist may be polyiC,polyICLC (Hiltonol®).

The chemotherapeutic agent may be a combination of carboplatin andtaxol.

The therapeutic monoclonal antibody specific for a tumor associatedantigen may be mAb-B43.13 (oregovomab), and the chemotherapeutic agentmay be a combination of carboplatin and taxol.

The immune homeostatic checkpoint inhibitor may be an anti-PDL-1antibody, an anti-CTLA-4 antibody, and anti-PD-1 antibody, orcombinations thereof.

The anti-PDL-1 antibody may be selected from the group consisting ofB7-H1 antibody, BMS-936559 antibody, MPDL3280A (atezolizumab) antibody,MEDI-4736 antibody, MSB0010718C antibody or combinations thereof; theanti-CTLA-4 antibody may be selected from the group consisting ofipilimumab or tremelimumab or combinations thereof, and the anti-PD-1antibody may be selected from the group consisting of Nivolumabantibody, pembrolizumab antibody, pidilizumab antibody or combinationsthereof, and AMP-224.

The a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor isselected from the group consisting of olaparib, niraparib, rucaparib,talazoparib, veliparib, CEP 9722, E7016, and BGB-290, or combinationsthereof.

The cancer may be ovarian cancer.

According to another embodiment, there is provided a therapeutic agentfor use in inhibiting tumor cancer growth in a patient, comprising animmune adjuvant and a therapeutic monoclonal antibody specific for atumor associated antigen, wherein the therapeutic agent may beadministered according to:

-   -   at least one sequential use of (a) followed by (b):    -   (a) a combination of the immune adjuvant and the therapeutic        monoclonal antibody specific for a tumor associated antigen;    -   (b) the immune adjuvant; and    -   a final use consisting of the therapeutic monoclonal antibody        specific for a tumor associated antigen,        wherein time between (a) and (b) is a time sufficient for        treatment of the patient with the immune adjuvant, and        wherein time between the (b) and the final use is from about 10        to about 14 weeks.

The therapeutic agent may further comprise another (a second) sequentialuse of (a) followed by (b) according to the present invention.

The therapeutic agent may further comprise another (a third) sequentialuse of (a) followed by (b) according to the present invention.

The therapeutic agent according to the present invention, may comprise:

-   -   a first, second and third sequential use of (a) followed by (b):    -   (a) the immune adjuvant and the therapeutic monoclonal antibody        specific for a tumor associated antigen;    -   (b) the immune adjuvant; and    -   a final use consisting the therapeutic monoclonal antibody        specific for a tumor associated antigen,        wherein time between (a) and (b) is from a time sufficient for        treatment of the patient with the immune adjuvant,        wherein time between (b) of the first use and (a) of the second        use, and (b) of the second use and (a) of the third use is a        time sufficient for treatment of the patient with the immune        adjuvant, and        wherein time between the third sequential use and the final use        is from about 10 to about 14 weeks.

The immune adjuvant may be a chemotherapeutic agent, animmunostimulatory compound, an immune homeostatic checkpoint inhibitor,or a combination thereof.

The therapeutic monoclonal antibody specific for a tumor associatedantigen may be an antibody specific to CA125.

The antibody specific to CA125 may be mAb-B43.13 (oregovomab).

The chemotherapeutic agent may be a platinum-based chemotherapy, taxol,doxorubicin, topotecan, a poly(adenosine diphosphate-ribose) polymerase(PARP) inhibitor, or combinations thereof.

The platinum-based chemotherapy comprises cisplatin, carboplatin,oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin,picoplatin, satraplatin, and combinations thereof.

The chemotherapeutic agent may be a combination of carboplatin andtaxol.

The therapeutic monoclonal antibody specific for a tumor associatedantigen may be mAb-B43.13 (oregovomab), and the chemotherapeutic agentmay be a combination of carboplatin and taxol.

The immunostimulatory compound may be a TLR3 agonist, a TLR4 agonist, orcombinations thereof.

The TLR3 agonist may be polyiC, polyICLC (Hiltonol®).

The immune homeostatic checkpoint inhibitor may be an anti-PDL-1antibody, an anti-CTLA-4 antibody, and anti-PD-1 antibody, orcombinations thereof.

The anti-PDL-1 antibody may be selected from the group consisting ofB7-H1 antibody, BMS-936559 antibody, MPDL3280A (atezolizumab) antibody,MEDI-4736 antibody, MSB0010718C antibody or combinations thereof.

The anti-CTLA-4 antibody may be selected from the group consisting ofipilimumab or tremelimumab or combinations thereof.

The anti-PD-1 antibody may be selected from the group consisting ofNivolumab antibody, pembrolizumab antibody, pidilizumab antibody orcombinations thereof, and AMP-224.

The a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor isselected from the group consisting of olaparib, niraparib, rucaparib,talazoparib, veliparib, CEP 9722, E7016, and BGB-290, or combinationsthereof.

The cancer may be ovarian cancer.

The following terms are defined below.

The terms “administration of” and/or “administering a” is intended tomean providing an antibody according to the present invention with orwithout additional compound(s) to a subject in need of treatment.

The term “composition” intended to mean a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combination of the specifiedingredients in the specified amounts. Such term in relation topharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s) and the inert ingredient(s) thatmake up the pharmaceutically acceptable carrier, as well as any productwhich results, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing an antibody according to the presentinvention and a pharmaceutically acceptable carrier. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The term “immune adjuvant” is intended to mean a component thatpotentiates the immune responses to an antigen and/or modulates ittowards the desired immune responses. It is a substance that acts toaccelerate, prolong, or enhance antigen-specific immune responses whenused in combination with specific antigens. In the context of thepresent invention, this includes chemotherapeutic agents such as forexample platinum-based chemotherapy, taxol, doxorubicin, topotecan, apoly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, orcombinations thereof, immunostimulatory compounds such as for exampleTLR3 agonist and TLR4 agonist, and their combinations, immunehomeostatic checkpoint inhibitor such as for example anti-PDL-1antibody, an anti-CTLA-4 antibody, and anti-PD-1 antibody, and theircombinations; or a combination thereof. In embodiments, the immuneadjuvant property(ies) of the immune adjuvant may be in addition toother therapeutic properties, such as for example cytotoxicity. That isto say, without wishing to be bound by theory, the immune adjuvants asdescribed herein may not only act as an immune adjuvant, but may haveother therapeutic properties for which, for example, it may be used intherapy. Such therapy may be, for example, as standard of care therapyfor a given cancer.

The term “chemotherapy regimen” is intended to mean combination ofseveral chemotherapeutic agents. The rationale behind such chemotherapyregimen is that different chemotherapy drugs work through differentcytotoxic mechanisms, and that the results of using multiple drugs willbe synergistic to some extent. Because they have different dose-limitingadverse effects, they can be given together at full doses inchemotherapy regimens. Chemotherapy regimen may include induction andmaintenance regimen.

The term “induction regimen” is intended to mean a chemotherapy regimenused for the initial treatment of a disease.

The term “maintenance regimen” is intended to mean the ongoing use ofchemotherapy to reduce the chances of a cancer recurring or to preventan existing cancer from continuing to grow.

In some embodiments, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans. Theterm “carrier” refers to a diluent, adjuvant, excipient, or vehicle withwhich the therapeutic is administered. Such pharmaceutical carriers canbe sterile liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. Water is a preferredcarrier when the pharmaceutical composition is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid carriers, particularly forinjectable solutions. Suitable pharmaceutical excipients include starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. The composition, if desired, can also contain minor amounts ofwetting or emulsifying agents, or pH buffering agents. Thesecompositions can take the form of solutions, suspensions, emulsion,tablets, pills, capsules, powders, sustained-release formulations andthe like. The composition can be formulated as a suppository, withtraditional binders and carriers such as triglycerides. Oral formulationcan include standard carriers such as pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, etc. Examples of suitable pharmaceutical carriersare described in “Remington's Pharmaceutical Sciences” by E. W. Martin.Such compositions will contain a therapeutically effective amount of theantibody or fragment thereof, preferably in purified form, together witha suitable amount of carrier so as to provide the form for properadministration to the patient. The formulation should suit the mode ofadministration.

The terms “inhibit”, “inhibition” or “inhibiting” as used herein in thecontext of the invention means to slow, hinder, restrain reduce orprevent. For example, “inhibiting growth” of a tumor cell as that termis used herein means to slow, hinder, restrain, reduce or prevent thetumor cell from growing.

The term “administering” as used herein refers to any action thatresults in exposing or contacting a composition containing a therapeuticmonoclonal antibody specific for a tumor associated antigen incombination with at least one immunostimulatory compound, and at leastone immune homeostatic checkpoint inhibitor, according to the inventionwith a pre-determined cell, cells, or tissue, typically mammalian. Asused herein, administering may be conducted in vivo, in vitro, or exvivo. For example, a composition may be administered by injection orthrough an endoscope. Administering also includes the direct applicationto cells of a composition according to the present invention. Forexample, during the course of surgery, tumor cells may be exposed. Inaccordance with an embodiment of the invention, these exposed cells (ortumors) may be exposed directly to a composition of the presentinvention, e.g., by washing or irrigating the surgical site and/or thecells, or by direct intra-tumoral injection of the therapeuticmonoclonal antibody specific for a tumor associated antigen incombination with at least one immunostimulatory compound, and at leastone immune homeostatic checkpoint inhibitor individually or in amixture.

The term “epitope” is intended to mean the portion of an antigen capableof being recognized by and bound by an antibody at one or more of theantibody's binding regions. Epitopes generally comprise chemicallyactive surface groupings of molecules such as amino acids or sugar sidechains and have specific three dimensional structure characteristics aswell as specific charge characteristics. In one embodiment, an epitopeof an antigen is a repetitive epitope. In one embodiment an epitope ofan antigen is a non-repetitive epitope.

The term “subject” as used herein, is a human patient or other animalsuch as another mammal with functional mast cells, basophils,neutrophils, eosinophils, monocytes, macrophages, dendritic cells, andLangerhans cells. In humans, the appropriate cells express the highaffinity receptor for IgG for the administered IgG antibody of theinvention, as well as IgE (FcεRI) for the administered IgE antibody ofthe invention.

As used herein, a reduction in growth kinetics, or complete eliminationof, a cancer tumor or a metastasized cell or tumor as used herein isdefined to mean that which is as understood in the art. For example, areduction in growth kinetics means a reduction in the exponentialgrowth, specific growth rate, or doubling time of a primary solid tumor,metastasized cell, or metastasized tumor relative to the exponentialgrowth, specific growth rate, or doubling time normally observed in vivoor in vitro for a given tumor type. Complete elimination of a tumor isthe absence of tumor presence, either by symptoms, physical exam, orradiographic imaging, in the presence of the therapeutic monoclonalantibody specific for a tumor associated antigen in combination with atleast one immunostimulatory compound, and at least one immunehomeostatic checkpoint inhibitor, where a tumor was previously seen tobe present by these detection methodologies.

The term “tumor-associated antigen” (TAA) as used herein can be any typeof cancer antigen that may be associated with a tumor as is known in theart and includes antigens found on the cell surface, including tumorcells, as well as soluble cancer antigens. Several cell surface antigenson tumors and normal cells have soluble counterparts. Such antigensinclude, but are not limited to those found on cancer-associatedfibroblasts (CAFs), tumor endothelial cells (TEC) and tumor-associatedmacrophages (TAM). Examples of cancer-associated fibroblasts (CAFs)target antigens include but are not limited to: carbonic anhydrase IX(CAIX); fibroblast activation protein alpha (FAPα); and matrixmetalloproteinases (MMPs) including MMP-2 and MMP-9. Examples of Tumorendothelial cell (TECs) target antigens include, but are not limited tovascular endothelial growth factor (VEGF) including VEGFR-1, 2, and 3;CD-105 (endoglin), tumor endothelia markers (TEMs) including TEM1 andTEM8; MMP-2; Survivin; and prostate-specific membrane antigen (PMSA).Examples of tumor associated macrophage antigens include, but are notlimited to: CD105; MMP-9; VEGFR-1, 2, 3 and TEM8. According to someembodiments, the tumor associated antigen may be CA125, folate bindingprotein (FBP), HER2/neu, MUC1 or PSA.

The term “time sufficient for treatment” or “a time sufficient fortreatment of the patient with the immune adjuvant” is intended to meanany period of time suitable to effect treatment with the immuneadjuvant. In embodiments, that time period may be the time of a cycleused in standard to care for the immune adjuvant (e.g. chemotherapy).Examples of standard of care treatments may be found for example inGynecologic Oncology Group Chemotherapy Procedures Manual, incorporatedherein by reference. The length of chemotherapy treatment is determinedby a variety of factors. These include the type of cancer, the extent ofcancer, the types of drugs that are given, as well as the expectedtoxicities of the drugs and the amount of time necessary to recover fromthese toxicities. Many chemotherapy treatment schedules (often referredto as Standard of Care (SOC), including the type and length ofchemotherapy treatment) have been determined through clinical trialsthat compared them and determined which had the most benefit and wasmost well tolerated. In general, chemotherapy treatment is given incycles. This allows the cancer cells to be attacked at their mostvulnerable times, and allows the body's normal cells time to recoverfrom the damage. There are really three issues regarding the cycle time,duration of the cycle, frequency of the cycle, and how many cycles.Duration of the cycle: chemotherapy treatment may be a single drug or acombination of drugs. The drugs may all be given on a single day,several consecutive days, or continuously as an outpatient or as aninpatient. Treatment could last minutes, hours, or days, depending onthe specific protocol. Frequency of the cycle: chemotherapy may repeatweekly, bi-weekly, or monthly. Usually, a cycle is defined in monthlyintervals. For example, two bi-weekly chemotherapy sessions may beclassified as one cycle. The number of cycles: In most cases, the numberof cycles—or the length of chemotherapy from start to finish—has beendetermined by research and clinical trials. When cure is the treatmentgoal. Adjuvant chemotherapy (therapy after surgery has removed allvisible cancer) may last 4-6 months. Adjuvant chemotherapy is common incancers of the breast and colon. In cancers of the testis, Hodgkin andnon-Hodgkin lymphoma, and leukemias, length of chemotherapy treatmentmay be up to a year. When there is visible disease, the length ofchemotherapy treatment will depend upon the response of the disease totherapy. If the disease disappears completely, chemotherapy may continuefor 1-2 cycles beyond this observation to maximize the chance of havingattacked all microscopic disease. If the disease shrinks but does notdisappear, chemotherapy will continue as long as it is tolerated and thedisease does not grow. If the disease grows, the chemotherapy will bestopped. As patients experience toxicities and blood cell counts, theactual timing of the cycles is sometimes delayed according thenecessities of each patient's circumstance. Depending on the health andwishes of the patient, either different drugs may be given to try tokill the cancer, or chemotherapy will be stopped and the goal changed tofocus on patient comfort. In an embodiment, for example, theadministration of the immune adjuvant therapy combining paclitaxel andcarboplatin is often performed in cycles of about 21 days (3 weeks).

Before describing the present invention in detail, a number of termswill be defined. As used herein, the singular forms “a”, “an”, and “the”include plural referents unless the context clearly dictates otherwise.

It is noted that terms like “preferably”, “commonly”, and “typically”are not utilized herein to limit the scope of the claimed invention orto imply that certain features are critical, essential, or evenimportant to the structure or function of the claimed invention. Rather,these terms are merely intended to highlight alternative or additionalfeatures that can or cannot be utilized in a particular embodiment ofthe present invention.

For the purposes of describing and defining the present invention it isnoted that the term “substantially” is utilized herein to represent theinherent degree of uncertainty that can be attributed to anyquantitative comparison, value, measurement, or other representation.The term “substantially” is also utilized herein to represent the degreeby which a quantitative representation can vary from a stated referencewithout resulting in a change in the basic function of the subjectmatter at issue.

Features and advantages of the subject matter hereof will become moreapparent in light of the following detailed description of selectedembodiments, as illustrated in the accompanying figures. As will berealized, the subject matter disclosed and claimed is capable ofmodifications in various respects, all without departing from the scopeof the claims. Accordingly, the drawings and the description are to beregarded as illustrative in nature, and not as restrictive and the fullscope of the subject matter is set forth in the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the present disclosure will becomeapparent from the following detailed description, taken in combinationwith the appended drawings, in which:

FIG. 1 illustrates a schematic of the Frontline ChemoimmunotherapyRandomized Phase II trial according to an embodiment of the presentinvention;

FIG. 2 illustrates the time to clinical relapse in the ITT population,for the CIT treatment arm (full line) and the SOC treatment arm (dashline);

FIG. 3 illustrates relapse free survival in the ITT population, for theCIT treatment arm (full line) and the SOC treatment arm (dash line);

FIG. 4 illustrates overall survival in the ITT population, for the CITtreatment arm (full line) and the SOC treatment arm (dash line);

FIG. 5 illustrates the time to clinical relapse in the US patients partof the ITT population, for the CIT treatment arm (full line) and the SOCtreatment arm (dash line);

FIG. 6 illustrates the time to clinical relapse in the Italian patientsof the ITT population, for the CIT treatment arm (full line) and the SOCtreatment arm (dash line);

FIG. 7 illustrates overall survival of patients with Tumor grade 3 and 4from the patients in the study group, for the CIT treatment arm (fullline) and the SOC treatment arm (dash line);

FIG. 8 illustrates time to clinical relapse of patients with FICO stageIIIC-IV from the patients in the study group, for the CIT treatment arm(full line) and the SOC treatment arm (dash line);

FIG. 9 illustrates a Forest plot of Time to clinical relapse (TTCR)hazard ratios by patient subgroups. Treatment 1=CIT; Treatment 2=SOC.

FIG. 10 illustrates a Forest plot of Relapse free survival (RFS) hazardratios by patient subgroups. Treatment 1=CIT; Treatment 2=SOC.

FIG. 11 illustrates a Forest plot of overall survival (OS) hazard ratiosby patient subgroups. Treatment 1=CIT; Treatment 2=SOC.

FIG. 12 illustrates the relapse free survival from the CIT group (leftgraph) and SOC group (right). The population from each group is segratedon the basis of the Neutrophil/lymphocyte ratio (NLR) at baseline andpatients' clinical outcome in terms of RFS using a cut-off value of3.612 for patients.

It will be noted that throughout the appended drawings, like featuresare identified by like reference numerals.

DETAILED DESCRIPTION

In embodiments there are disclosed a method of inhibiting cancer tumorgrowth in a patient in need thereof, comprising:

-   -   at least a first treatment comprising steps a) and b):    -   a) administering to the patient an immune adjuvant in        combination with a therapeutic monoclonal antibody specific for        a tumor associated antigen; and    -   b) administering to the patient the immune adjuvant; and    -   a final treatment consisting of administering to the patient the        therapeutic monoclonal antibody specific for a tumor associated        antigen,        wherein time between step a) and step b) is a time sufficient        for treatment of the patient with the immune adjuvant, and        wherein time between the step b) and the final treatment is from        about 10 to about 14 weeks.

According to an embodiment, the method may further comprise a secondtreatment comprising steps a) and b), with a time sufficient fortreatment of the patient with the immune adjuvant between step b) of thefirst treatment and step a) of the second treatment. In a preferredembodiment, the method further comprises a third treatment comprisingsteps a) and b), with a time sufficient for treatment of the patientwith the immune adjuvant between step b) of the second treatment andstep a) of the third treatment.

According to another embodiment, there is disclosed a method ofinhibiting cancer tumor growth in a patient in need thereof, comprising:

-   -   a first, second and third treatment comprising steps a) and b):    -   a) administering to the patient an immune adjuvant in        combination with a therapeutic monoclonal antibody specific for        an tumor associated antigen; and    -   b) administering to the patient the immune adjuvant; and    -   a final treatment consisting of administering the therapeutic        monoclonal antibody specific for a tumor associated antigen,        wherein time between step a) and step b) is a time sufficient        for treatment of the patient with the immune adjuvant,        wherein time between step b) of the first treatment and step a)        of the second treatment, and step b) of the second treatment and        step a) of the third treatment is a time sufficient for        treatment of the patient with the immune adjuvant, and wherein        time between the at least one treatment and the final treatment        is from about 10 to about 14 weeks.

In embodiments of the present invention, the term “in combination” isintended to mean that the therapeutic monoclonal antibody specific foran tumor associated antigen and the immune adjuvant are administeredduring the same treatment or treatment cycle. This includesadministration conditions where the immune adjuvant is administeredfirst, followed by administration of the therapeutic monoclonal antibodyspecific for an tumor associated antigen. This also includesadministration conditions where the therapeutic monoclonal antibodyspecific for an tumor associated antigen is administered first, followedby the immune adjuvant, or conditions where the immune adjuvant isadministered at the same time as the therapeutic monoclonal antibodyspecific for an tumor associated antigen. This also includesadministration conditions where the immune adjuvant is a combination ofcompounds, and where a first drug may be administered, followed by thetherapeutic monoclonal antibody specific for an tumor associatedantigen, followed by a second drug; or where a first drug may beadministered, followed by a second drug follow by the therapeuticmonoclonal antibody specific for an tumor associated antigen; or wherethe therapeutic monoclonal antibody specific for an tumor associatedantigen is administered first, followed by a first drug, followed by asecond drug. Alternatively, all components of the treatment could beadministered at the same time. Similar administration conditions couldbe used for other standard of care therapy including more than 2 drugs.

According to embodiments, the time sufficient for treatment of thepatient with the immune adjuvant may be as defined above. In aparticular embodiment, the time sufficient for treatment of the patientwith the immune adjuvant may be about 3 weeks, or about 21 days.

According to embodiments, time between step b) and the final treatmentmay be from about 10 to about 14 weeks, or from about 10 to about 13weeks, or about 10 to about 12 weeks, or about 10 to about 11 weeks, orabout 11 to 14 weeks, or about 11 to 13 weeks, or about 11 to 12 weeks,or about 12 to 14 weeks, or about 12 to 13 weeks, or about 10 weeks, orabout 11 weeks, or about 12 weeks, or about 13 weeks, or about 14 weeks,or about 2.5 month, about 3 months, about 3.5 months.

The inventors have unexpectedly discovered that monoclonal antibodyspecific for a tumor associated antigen in combination with an immuneadjuvant can inhibit tumor growth. Without being bound by theory, thecombination of monoclonal antibodies specific for a tumor associatedantigen with the immune adjuvant in accordance with the inventionappears to be protecting subjects against growth of tumors. Theinvention is unique and unexpected in that it provides for a synergisticeffect between these two immune modulators to greatly enhance patientsurvival. This is in stark contrast to the use of chemotherapy alonefollowed by monoclonal antibodies specific for a tumor associatedantigen alone after the initial chemotherapy treatment, which showed noimprovements in clinical outcome in advanced ovarian cancer (Berek etal. J Clin Onc 27:418-425, 2009). This is also in contrast with thestudy of Braly et al. (J Immunother 2009; 32:54-65) which prescribed 8cycles of chemotherapy including immunotherapy at cycles 1, 3, and 5;two additional rounds of chemotherapy and immunotherapy at 12 and 24weeks past cycle 5, followed by follow-up additional immunotherapy (6rounds) for up to two years—for a total of 11 doses of immunotherapy.The present invention includes a maximum of 6 cycles of immune adjuvanttreatment (in this case, chemotherapy), combined with immunotherapy atcycles 1, 3 and 5, and a final round of immunotherapy alone at 12 pastcycle 5, for a total of 4 rounds of immunotherapy, with no follow-up ormaintenance therapy (See FIG. 1). Unexpectedly, the treatmentdramatically improved clinical outcome in advanced ovarian cancerpatients. In particular, a direct comparison may be made between thestudy of Braly et al., where the present invention display much improvedprogression-free survival.

A reduction in growth kinetics, or complete elimination of, a cancertumor or a metastasized cell or tumor as used herein is defined to meanthat which is as understood in the art. For example, a reduction ingrowth kinetics means a reduction in the exponential growth, specificgrowth rate, or doubling time of a primary solid tumor, metastasizedcell, or metastasized tumor relative to the exponential growth, specificgrowth rate, or doubling time normally observed in vivo or in vitro fora given tumor type. Complete elimination of a tumor is the absence oftumor presence, either by symptoms, physical exam, or radiographicimaging, in the presence of the therapeutic monoclonal antibody specificfor a tumor associated antigen in combination with at least oneimmunostimulatory compound, and at least one immune homeostaticcheckpoint inhibitor, where a tumor was previously seen to be present bythese detection methodologies.

According to an embodiment, antigen specific antibodies can be used toenhance T cell reactivity to self-antigens, especially in patientswithout mutations in human tumor associated antigens (TAA) that areidentical with self. By binding self-antigens with low dose immunogenicantibodies, the pool of available tumor specific T cells is enhanced andcheckpoint interference can lead to amplified immunity and enhancedclinical activity of the therapy.

The combined effect of the immune modulator results in the inhibition oftumor growth and/or the facilitation of tumor destruction, in whole orin part.

The term “therapeutic monoclonal antibody specific for a tumorassociated antigen” as used in the invention is a monoclonal antibodythat may be any suitable monoclonal antibody, such as for example anIgG, and/or an IgE (which comprises the human Fc epsilon (c) constantregion) and also comprises variable regions comprising at least oneantigen binding region specific for a tumor-associated antigen (TAA)that is a cell surface antigen or a soluble cancer antigen located inthe tumor microenvironment or otherwise in close proximity to the tumorbeing treated.

The terms “monoclonal antibody” or “monoclonal antibodies” as usedherein refer to a preparation of antibodies of single molecularcomposition. A monoclonal antibody composition displays a single bindingspecificity and affinity for a particular epitope. The monoclonalantibodies of the present invention are preferably chimeric, humanized,or fully human in order to bind to human antibody receptors such as thehuman Fc epsilon receptors when the subject host is a human. Humanizedand fully human antibodies are also useful in reducing immunogenicitytoward the murine components of, for example, a chimeric antibody, whenthe host subject is human. Monoclonal antibodies may be prepared bystandard techniques including, but not limited to, recombinantly andsynthetically.

The term “chimeric monoclonal antibody” refers to antibodies displayinga single binding specificity, which have one or more regions derivedfrom one antibody and one or more regions derived from another antibody.In one embodiment of the invention, the constant regions are derivedfrom the human epsilon (c) constant region (heavy chain) and human kappaor lambda (light chain) constant regions. The variable regions of achimeric IgE monoclonal antibody of the invention are typically ofnon-human origin such as from rodents, for example, mouse (murine),rabbit, rat or hamster.

As used herein, “humanized” monoclonal antibodies comprise constantregions that are derived from human epsilon constant region (heavychain) and human kappa or lambda (light chain) constant regions. Thevariable regions of the antibodies preferably comprise a framework ofhuman origin and antigen binding regions (CDRs) of non-human origin.

Fully human or human-like antibodies may be produced through vaccinationof genetically engineered animals such as mouse lines produced at Amgen)and Bristol-Myers Squibb which contain the human immunoglobulin geneticrepertoire and produce fully human antibodies in response tovaccination. Further, the use of phage display libraries incorporatingthe coding regions of human variable regions which can be identified andselected in an antigen-screening assay to produce a human immunoglobulinvariable region binding to a target antigen.

The term “antigen binding region” refers to that portion of an antibodyas used in the invention which contains the amino acid residues thatinteract with an antigen and confer on the antibody its specificity andaffinity for the antigen. The antibody region includes the “framework”amino acid residues necessary to maintain the proper confirmation of theantigen binding residues.

An “antigen” is a molecule or portion of a molecule capable of beingbound by an antibody, which is additionally capable of inducing ananimal to produce antibody capable of binding to an epitope of thatantigen. An antigen can have one or more epitopes that are the same ordifferent. In a preferred embodiment, the antibodies of the inventionare specific for a single epitope. In one embodiment, the antigen is acapable of being bound by an antibody as used in the invention to forman immune complex that in combination with at least oneimmunostimulatory compound, and at least one immune homeostaticcheckpoint inhibitor, is capable of inhibiting cancer tumor growth. Inone embodiment, the antigen, on its own, may not be capable ofstimulating an immune response for any number of reasons, for example,the antigen is a “self” antigen, not normally recognized by the immunesystem as requiring response or the immune system has otherwise becometolerant to the antigen and does not mount an immune response. Inanother embodiment, the antigen is MUC1.

The term “epitope” is meant to refer to that portion of an antigencapable of being recognized by and bound by an antibody at one or moreof the antibody's binding regions. Epitopes generally comprisechemically active surface groupings of molecules such as amino acids orsugar side chains and have specific three-dimensional structurecharacteristics as well as specific charge characteristics. In oneembodiment, an epitope of an antigen is a repetitive epitope. In oneembodiment, an epitope of an antigen is a non-repetitive epitope.

Therefore, in embodiments, the therapeutic monoclonal antibody specificfor a tumor associated antigen may be any suitable antibody. Accordingto another embodiment, the therapeutic monoclonal antibody specific fora tumor associated antigen may be any suitable IgG and/or IgE antibody,or any other therapeutic isotypes. According to an embodiment, the tumorassociated antigen may be CA125, folate binding protein (FBP), HER2/neu,MUC1 or PSA. According to another embodiment, the monoclonal antibodyspecific for a tumor associated antigen may be for example mAb-AR20.5,mAb-B43.13, mAb 3C6.hlgE, mAb-4H5.hlgE, mAb-AR47.47, as well as themouse/human chimeric anti-PSA IgE containing the variable regions ofAR47.47 described in Daniels-Wells et al. (BMC Cancer. 2013 Apr. 17;13:195. doi: 10.1186/1471-2407-13-195). According to another embodiment,the therapeutic tumor associated antigen specific antibody may be achimeric monoclonal antibody, a humanized monoclonal antibody or a fullyhuman monoclonal antibody.

Methods for raising antibodies, such as murine antibodies to an antigen,and for determining if a selected antibody binds to a unique antigenepitope are well known in the art.

Screening for the desired antibody can be accomplished by techniquesknown in the art, e.g., radioimmunoassay, ELISA (enzyme-linkedimmunosorbant assay), “sandwich” immunoassays, immunoradiometric assays,gel diffusion precipitin reactions, immunodiffusion assays, in situimmunoassays (using colloidal gold, enzyme or radioisotope labels, forexample), western blots, precipitation reactions, agglutination assays(e.g., gel agglutination assays, hemagglutination assays), complementfixation assays, immunofluorescence assays, protein A assays, andimmunoelectrophoresis assays, etc. Many means are known in the art fordetecting binding in an immunoassay and are within the scope of thepresent invention.

For preparation of monoclonal antibodies, any technique that providesfor the production of antibody molecules by continuous cell lines inculture may be used (see, e.g., Antibodies—A Laboratory Manual, Harlowand Lane, eds., Cold Spring Harbor Laboratory Press: Cold Spring Harbor,N.Y., 1988). These include but are not limited to the hybridomatechnique originally developed by Kohler and Milstein (1975, Nature256:495-497), as well as the trioma technique, the human B-cellhybridoma technique (Kozbor et al., 1983, Immunology Today, 4:72), andthe EBV-hybridoma technique to produce human monoclonal antibodies (Coleet al., 1985, in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss,Inc., pp. 77-96). In an additional embodiment of the invention,monoclonal antibodies can be produced in germ-free animals utilizingrecent technology (PCT/US90/02545). According to the invention, humanantibodies may be used and can be obtained by using human hybridomas(Cote et al., 1983, Proc. Natl. Acad. Sci. U.S.A., 80:2026-2030) or bytransforming human B cells with EBV virus in vitro (Cole et al., 1985,in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, pp. 77-96).In fact, according to the invention, techniques developed for theproduction of “chimeric antibodies” (Morrison et al., 1984, J.Bacteriol. 159: 870; Neuberger et al., 1984, Nature 312:604-608; Takedaet al., 1985, Nature 314: 452-454) by splicing the genes from a mouseantibody molecule specific for a polypeptide together with genes from ahuman antibody molecule of appropriate biological activity can be used;such antibodies are within the scope of this invention.

In one embodiment, therapeutic monoclonal antibodies specific for atumor associated antigen in accordance with the present invention areexpressed by a positive transfectoma which is identified byenzyme-linked immunosorbent assay (ELISA) and Western Blot. The positivetransfectoma will be cloned by limited dilution for highest productivityand selected for antibody production. As used herein a “transfectoma”includes recombinant eukaryotic host cells expressing the antibody, suchas Chinese hamster ovary (CHO) cells and NS/O myeloma cells. Suchtransfectoma methodology is well known in the art (Morrison, S. (1985)Science, 229:1202). Previously published methodology used to generatemouse/human chimeric or humanized antibodies has yielded the successfulproduction of various human chimeric antibodies or antibody fusionproteins (Helguera G, Penichet ML., Methods Mol. Med. (2005)109:347-74).

In general, chimeric mouse-human monoclonal antibodies (i.e., chimericantibodies) can be produced by recombinant DNA techniques known in theart. For example, a gene encoding the Fc constant region of a murine (orother species) monoclonal antibody molecule is digested with restrictionenzymes to remove the region encoding the murine Fc, and the equivalentportion of a gene encoding a human Fc constant region is substituted.(See Robinson et al., International Patent Publication PCT/US86/02269;Akira, et al., European Patent Application 184,187; Taniguchi, M.,European Patent Application 171, 496; Morrison et al., European PatentApplication 173,494; Neuberger et al.; Cabilly et al. U.S. Pat. No.4,816,567; Cabilly et al., European Patent Application 125,023; Betteret al. (1988 Science, 240:1041-1043); Liu et al. (1987) PNAS,84:3439-3443; Liu et al., 1987, J. Immunol., 139:3521-3526; Sun et al.(1987) PNAS, 84:214-218; Nishimura et al., 1987, Canc. Res.,47:999-1005; Wood et al. (1985) Nature, 314:446-449; and Shaw et al.,1988, J. Natl Cancer Inst., 80:1553-1559).

The chimeric antibody can be further humanized by replacing sequences ofthe Fv variable region which are not directly involved in antigenbinding with equivalent sequences from human Fv variable regions.General reviews of humanized chimeric antibodies are provided byMorrison, S. L., 1985, Science, 229:1202-1207 and by Oi et al., 1986,BioTechniques, 4:214. Those methods include isolating, manipulating, andexpressing the nucleic acid sequences that encode all or part ofimmunoglobulin Fv variable regions from at least one of a heavy or lightchain. Sources of such nucleic acid are well known to those skilled inthe art and, for example, may be obtained from 7E3, ananti-GPII_(b)III_(a) antibody producing hybridoma. The recombinant DNAencoding the chimeric antibody, or fragment thereof, can then be clonedinto an appropriate expression vector. Suitable humanized antibodies canalternatively be produced by CDR substitution (U.S. Pat. No. 5,225,539;Jones et al. 1986 Nature, 321:552-525; Verhoeyan et al. 1988 Science,239:1534; and Beidler et al. 1988 J. Immunol., 141:4053-4060).

In a preferred embodiment, the therapeutic monoclonal antibody specificfor a tumor associated antigen is an antibody specific to CA125 (MUC16).The antibody specific to CA125 may be mAb-B43.13 (oregovomab).

As used herein, an “effective amount” of a therapeutic monoclonalantibody specific for a tumor associated antigen of the invention isthat amount sufficient to recognize and bind the epitope of the TAA thatis a cell surface antigen and induce, elicit, or enhance the referencedimmune response in accordance with the invention.

In embodiments, the immune adjuvant may be a chemotherapeutic agent, animmunostimulatory compound, an immune homeostatic checkpoint inhibitor,or a combination thereof. According to an embodiment, thechemotherapeutic agent may be a platinum-based chemotherapy, such as forexample cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatintetranitrate, phenanthriplatin, picoplatin, satraplatin, andcombinations thereof. It may also be taxol (paclitaxel), doxorubicin,topotecan, a poly(adenosine diphosphate-ribose) polymerase (PARP)inhibitor, or combinations of each of the above chemotherapeutic agents.Examples of PARP inhibitors include, but are not limited to olaparib(AZD-2281 or Lynparza™), niraparib (MK-4827), rucaparib (AG014699 orRubraca™), talazoparib (BMN-673), veliparib (ABT-888), CEP 9722, E7016,and BGB-290. Also contemplated as chemotherapeutic agents are cytotoxictherapeutic agents which include, but are not limited to, angiogenesisinhibitors, antiproliferative agents, kinase inhibitors, receptortyrosine kinase inhibitors, aurora kinase inhibitors, polo-like kinaseinhibitors, bcr-abl kinase inhibitors, growth factor inhibitors, COX-2inhibitors, non-steroidal anti-inflammatory drugs (NSAIDS), antimitoticagents, alkylating agents, antimetabolites, intercalating antibiotics,platinum containing agents, growth factor inhibitors, ionizingradiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors,biologic response modifiers, immunologicals, antibodies, hormonaltherapies, retinoids/deltoids plant alkaloids, proteasome inhibitors,HSP-90 inhibitors, histone deacetylase inhibitors (HDAC) inhibitors,purine analogs, pyrimidine analogs, MEK inhibitors, CDK inhibitors,ErbB2 receptor inhibitors, mTOR inhibitors and combinations thereof aswell as other antitumor agents.

Angiogenesis inhibitors include, but are not limited to, EGFRinhibitors, PDGFR inhibitors, VEGFR inhibitors, TTE2 inhibitors, IGFIRinhibitors, matrix metalloproteinase 2 (MMP-2) inhibitors, matrixmetalloproteinase 9 (MMP-9) inhibitors, thrombospondin analogs such asthrombospondin-1 andN-Ac-Sar-Gly-Val-D-allolle-Thr-Nva-He-Arg-Pro-NHCH2CH3 or a salt thereofand analogues of N-Ac-Sar-Gly-Val-D-allolle-Thr-Nva-Ile-Arg-PrO-NHCH2CH3such as N-Ac-GlyVal-D-alle-Ser-Gln-Ile-Arg-ProNHCH2CH3 or a saltthereof.

Examples of EGFR inhibitors include, but are not limited to, Iressa(gefitinib), Tarceva (erlotinib or OSI-774), Icotinib, Erbitux(cetuximab), EMD-7200, ABX-EGF, HR3, IgA antibodies, TP-38 (IVAX), EGFRfusion protein, EGF-vaccine, anti-EGFr immunoliposomes and Tykerb(lapatinib).

Examples of PDGFR inhibitors include, but are not limited to, CP-673,451and CP-868596.

Examples of VEGFR inhibitors include, but are not limited to, Avastin(bevacizumab), Sutent (sunitinib, SUI 1248), Nexavar (sorafenib,BAY43-9006), CP-547,632, axitinib (AG13736), Apatinib, cabozantinib,Zactima (vandetanib, ZD-6474), AEE788, AZD-2171, VEGF trap, Vatalanib(PTK-787, ZK-222584), Macugen, M862, Pazopanib (GW786034), ABT-869 andangiozyme.

Examples of thrombospondin analogs include, but are not limited to,TSP-I and ABT-510.

Examples of aurora kinase inhibitors include, but are not limited to,VX-680, AZD-1152 and MLN-8054. Example of polo-like kinase inhibitorsinclude, but are not limited to, BI-2536.

Examples of bcr-abl kinase inhibitors include, but are not limited to,Gleevec (imatinib) and Dasatinib (BMS354825).

Examples of platinum containing agents includes, but are not limited to,cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin,Eloxatin (oxaliplatin) or satraplatin.

Examples of mTOR inhibitors includes, but are not limited to, CCI-779,rapamycin, temsirolimus, everolimus, RAD001, INK-128 and ridaforolimus.

Examples of HSP-90 inhibitors includes, but are not limited to,geldanamycin, radicicol, 17-AAG, KOS-953, 17-DMAG, CNF-101, CNF-1010,17-AAG-nab, NCS-683664, Mycograb, CNF-2024, PU3, PU24FC1, VER49009,IPI-504, SNX-2112 and STA-9090.

Examples of histone deacetylase inhibitors (HDAC) includes, but are notlimited to, Suberoylanilide hydroxamic acid (SAHA), MS-275, valproicacid, TSA, LAQ-824, Trapoxin, tubacin, tubastatin, ACY-1215 andDepsipeptide.

Examples of MEK inhibitors include, but are not limited to, PD325901,ARRY-142886, ARRY-438162 and PD98059.

Examples of CDK inhibitors include, but are not limited to,flavopyridol, MCS-5A, CVT-2584, seliciclib (CYC-202, R-roscovitine),ZK-304709, PHA-690509, BMI-1040, GPC-286199, BMS-387,032, PD0332991 andAZD-5438.

Examples of COX-2 inhibitors include, but are not limited to, CELEBREX™(celecoxib), parecoxib, deracoxib, ABT-963, MK-663 (etoricoxib), COX-189Lumiracoxib), BMS347070, RS 57067, NS-398, Bextra (valdecoxib),paracoxib, Vioxx (rofecoxib), SD-8381,4-Methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl-1H-pyrrole, T-614,JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etoricoxib).

Examples of non-steroidal anti-inflammatory drugs (NSAIDs) include, butare not limited to, Salsalate (Amigesic), Diflunisal (Dolobid),Ibuprofen (Motrin), Ketoprofen (Orudis), Nabumetone (Relafen), Piroxicam(Feldene), Naproxen (Aleve, Naprosyn), Diclofenac (Voltaren),Indomethacin (Indocin), Sulindac (Clinoril), Tolmetin (Tolectin),Etodolac (Lodine), Ketorolac (Toradol) and Oxaprozin (Daypro).

Examples of ErbB2 receptor inhibitors include, but are not limited to,CP-724-714, CI-1033, (canertinib), Herceptin (trastuzumab), Om itarg(2C4, petuzumab), TAK-165, GW-572016 (lonafarnib), GW-282974, EKB-569,PI-166, dHER2 (HER2 Vaccine), APC8024 (HER2 Vaccine), anti-HER/2neubispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecficantibodies, mAB AR-209 and mAB 2B-1.

Examples of alkylating agents include, but are not limited to, nitrogenmustard N-oxide, cyclophosphamide, ifosfamide, trofosfamide,Chlorambucil, melphalan, busulfan, mitobronitol, carboquone, thiotepa,ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280,apaziquone, brostallicin, bendamustine, carmustine, estramustine,fotemustine, glufosfamide, KW-2170, mafosfamide, and mitolactol,carmustine (BCNU), lomustine (CCNU), Busulfan, Treosulfan, Decarbazineand Temozolomide.

Examples of antimetabolites include but are not limited to,methotrexate, 6-mercaptopurine riboside, mercaptopurine, uracilanalogues such as 5-fluorouracil (5-FU) alone or in combination withleucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine,cytarabine ocfosfate, enocitabine, S-I, Alimta (premetrexed disodium,LY231514, MTA), Gemzar (gemcitabine), fludarabine, 5-azacitidine,capecitabine, cladribine, clofarabine, decitabine, eflornithine,ethnylcytidine, cytosine arabinoside, hydroxyurea, TS-I, melphalan,nelarabine, nolatrexed, ocfosate, disodium premetrexed, pentostatin,pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine,vincristine, vinorelbine, mycophenolic acid, tiazofurin, Ribavirin,EICAR, hydroxyurea and deferoxamine.

Examples of antibiotics include intercalating antibiotics but are notlimited to, aclarubicin, actinomycins such as actinomycin D, amrubicin,annamycin, adriamycin, bleomycin a, bleomycin b, daunorubicin,doxorubicin, elsamitrucin, epirbucin, glarbuicin, idarubicin, mitomycinC, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin,stimalamer, streptozocin, valrubicin, zinostatin and combinationsthereof.

Examples of topoisomerase inhibiting agents include, but are not limitedto, one or more agents selected from the group consisting ofaclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin,9-am inocamptothecin, diflomotecan, irinotecan HCL (Camptosar),edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan,lurtotecan, orathecin (Supergen), BN-80915, mitoxantrone, pirarbucin,pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide and topotecan.

Examples of antibodies include, but are not limited to, Rituximab,Cetuximab, Bevacizumab, Trastuzimab, specific CD40 antibodies andspecific IGFIR antibodies,

Examples of hormonal therapies include, but are not limited to,exemestane (Aromasin), leuprolide acetate, anastrozole (Arimidex),fosrelin (Zoladex), goserelin, doxercalciferol, fadrozole, formestane,tamoxifen citrate (tamoxifen), Casodex, Abarelix, Trelstar, finasteride,fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole, flutamide,bicalutamide, megesterol, mifepristone, nilutamide, dexamethasone,predisone and other glucocorticoids.

Examples of retinoids/deltoids include, but are not limited to,seocalcitol (EB 1089, CB 1093), lexacalcitrol (KH 1060), fenretinide,Aliretinoin, Bexarotene and LGD-1550.

Examples of plant alkaloids include, but are not limited to,vincristine, vinblastine, vindesine and vinorelbine.

Examples of proteasome inhibitors include, but are not limited to,bortezomib (Velcade), MGI 32, NPI-0052 and PR-171.

Examples of immunologicals include, but are not limited to, interferonsand numerous other immune enhancing agents. Interferons includeinterferon alpha, interferon alpha-2a, interferon, alpha-2b, interferonbeta, interferon gamma-1a, interferon gamma-1 b (Actimmune), orinterferon gamma-nl and combinations thereof. Other agents includefilgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin,alemtuzumab, BAM-002, decarbazine, daclizumab, denileukin, gemtuzumabozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanomavaccine (Corixa), molgramostim, OncoVAC-CL, sargaramostim, tasonermin,tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab,mitumomab, oregovomab, pemtumomab (Y-muHMFGI), Provenge (Dendreon),CTLA4 (cytotoxic lymphocyte antigen 4) antibodies and agents capable ofblocking CTLA4 such as MDX-010.

Examples of biological response modifiers are agents that modify defensemechanisms of living organisms or biological responses, such assurvival, growth, or differentiation of tissue cells to direct them tohave anti-tumor activity. Such agents include krestin, lentinan,sizofrran, picibanil and ubenimex.

Examples of pyrimidine analogs include, but are not limited to,5-Fluorouracil,

Floxuridine, Doxifluridine, Ratitrexed, cytarabine (ara C), Cytosinearabinoside, Fludarabine, and Gemcitabine.

Examples of purine analogs include but are not limited to,Mercaptopurine and thioguanine.

Examples of antimitotic agents include, but are not limited to, ABT-751,paclitaxel, docetaxel, epothilone D (KOS-862) and ZK-EPO.

In a preferred embodiment, the chemotherapeutic agent is a combinationof carboplatin and taxol. In another preferred embodiment, thetherapeutic monoclonal antibody specific for a tumor associated antigenis mAb-B43.13 (oregovomab), and the chemotherapeutic agent is acombination of carboplatin and taxol

In embodiments, the immune adjuvant may also be an immunostimulatorycompound. According to an embodiment, the present invention includesimmunostimulatory compounds. Immunostimulatory compounds are compoundhaving the capacity to stimulate or elicit an immune response. As usedherein, the term relates to exemplary immunostimulatory compounds thatinclude toll-like receptor (TLR) agonists (e.g., TLR3, TLR4, TLR7,TLR9), N-acetylmuramyl-L-alanine-D-isoglutamine (MDP),lipopolysaccharides (LPS), genetically modified and/or degraded LPS,alum, glucan, colony stimulating factors (e.g., EPO, GM-CSF, G-CSF,M-CSF, pegylated G-CSF, SCF, IL-3, IL6, PIXY 321), interferons (e.g.,gamma-interferon, alpha-interferon), interleukins (e.g., IL-2, IL-7,IL-12, IL-15, IL-18), MHC Class II binding peptides, saponins (e.g.,QS21), unmethylated CpG sequences, 1-methyl tryptophan, arginaseinhibitors, cyclophosphamide, antibodies that block immunosuppressivefunctions (e.g., anti-CTLA4 antibodies, anti-TGF-beta, etc.), andmixtures of two or more thereof.

In one preferred embodiment the immunostimulatory compound is a TLR3agonist. In preferred embodiments, the TLR3 agonist for use according tothe invention is a double stranded nucleic acid selected from the groupconsisting of: polyinosinic acid and polycytidylic acid, polyadenylicacid and polyuridylic acid, polyinosinic acid analogue and polycytidylicacid, polyinosinic acid and polycytidylic acid analogue, polyinosinicacid analogue and polycytidylic acid analogue, polyadenylic acidanalogue and polyuridylic acid, polyadenylic acid and polyuridylic acidanalogue, and polyadenylic acid analogue and polyuridylic acid analogue.Specific examples of double-stranded RNA as TLR3 agonists furtherinclude Polyadenur (Ipsen) and Ampligen (Hemispherx). Polyadenur is apolyA/U RNA molecule, i.e., contains a polyA strand and a polyU strand.Ampligen is disclosed for instance in EP 281 380 or EP 113 162. Inanother preferred embodiment, the TLR3 agonist may be Poly (I:C)LC orpolyIC (Hiltonol®), which is a synthetic complex ofcarboxymethylcellulose, polyinosinic-polycytidylic acid, andpoly-L-lysine double-stranded RNA. Poly (I:C)LC may stimulate therelease of cytotoxic cytokines and, by inducing interferon-gammaproduction, may increase the tumoricidal activities of variousimmunohematopoietic cells.

In one embodiment the immunostimulatory compound is a TLR4 agonist.Exemplary TLR4 agonists include taxanes such as paclitaxel anddocetaxal, lipopolysaccharides (LPS); E. coli LPS; and P. gingivalisLPS.

As used herein, an “effective amount” of an immunostimulatory compoundof the invention is that amount sufficient to induce, elicit, or enhancethe referenced immune response in accordance with the invention.

According to another embodiment, the present invention includes immunehomeostatic checkpoint inhibitors. Immune homeostatic checkpointinhibitors are monoclonal antibodies (mAb) directed to immune checkpointmolecules, which are expressed on immune cells and mediate signals toattenuate excessive immune reactions. According to an embodiment, immunehomeostasis checkpoint inhibition may be performed with inhibitorymonoclonal antibodies directed at the inhibitory immune receptorsCTLA-4, PD-1, and PDL-1. According to some embodiments, such inhibitorshave emerged as successful treatment approaches for patients withadvanced melanoma. According to an embodiment, the immune homeostaticcheckpoint inhibitors may be one of an anti-CTLA-4, anti-PD-1, and/oranti-PDL-1 antibody. According to an embodiment, the anti-CTLA-4antibody may be Ipilimumab or tremelimumab or combinations thereof.According to another embodiment, the anti-PDL-1 antibody may be B7-H1antibody, BMS-936559 antibody, MPDL3280A (atezolizumab) antibody,MEDI-4736 antibody, MSB0010718C antibody or combinations thereof.According to another embodiment, the anti-PD-1 antibody may be Nivolumabantibody, pembrolizumab antibody, pidilizumab antibody or combinationsthereof. In addition, PD-1 may also be targeted with AMP-224, which is aPD-L2-IgG recombinant fusion protein. Additional antagonists ofinhibitory pathways in the immune response are being advanced throughclinical development. IMP321 is a soluble LAG-3 Ig fusion protein andMHC class II agonist, which is used to increase an immune response totumors. LAG3 is an immune checkpoint molecule. Lirilumab is anantagonist to the KIR receptor and BMS 986016 is an antagonist of LAG3.A third inhibitory checkpoint pathway is the TIM-3-Galectin-9 pathwaythat is also a promising target for checkpoint inhibition. RX518 targetsand activates the glucocorticoid-induced tumor necrosis factor receptor(GITR), a member of the TNF receptor superfamily that is expressed onthe surface of multiple types of immune cells, including regulatory Tcells, effector T cells, B cells, natural killer (NK) cells, andactivated dendritic cells.

As used herein, an “effective amount” of an immune homeostaticcheckpoint inhibitor of the invention is that amount sufficient toinduce, elicit, or enhance the referenced immune response in accordancewith the invention.

According to an embodiment, the method of the present invention is forthe treatment of any cancer, and preferably for the treatment of ovariancancer.

According to yet another embodiment, the present invention alsoencompasses composition for use for inhibiting cancer tumor growth in apatient in need thereof, the composition comprising a therapeuticmonoclonal antibody specific for a tumor associated antigen, at leastone immune adjuvant.

Such compositions comprise a therapeutically effective amount of atherapeutic monoclonal antibody specific for a tumor associated antigen,and at least one immune adjuvant and may also include a pharmaceuticallyacceptable carrier. In one preferred embodiment, the pharmaceuticalcomposition comprises a therapeutic monoclonal antibody thatspecifically binds to CA125.

In accordance with a method or use of the invention compositionscomprising the therapeutic monoclonal antibody specific for a tumorassociated antigen, the immune adjuvant of the invention may beadministered to the patient by any immunologically suitable route. Forexample, they may be introduced into the patient by an intravenous,subcutaneous, intraperitoneal, intrathecal, intravesical, intradermal,intramuscular, or intralymphatic routes, alone or as combination. Thecomposition may be in solution, tablet, aerosol, or multi-phaseformulation forms. Liposomes, long-circulating liposomes,immunoliposomes, biodegradable microspheres, micelles, or the like mayalso be used as a carrier, vehicle, or delivery system. Furthermore,using ex vivo procedures well known in the art, blood or serum from thepatient may be removed from the patient; optionally, it may be desirableto purify the antigen in the patient's blood; the blood or serum maythen be mixed with a composition that includes a binding agent accordingto the invention; and the treated blood or serum is returned to thepatient. The invention should not be limited to any particular method ofintroducing the binding agent into the patient.

In a preferred embodiment, the composition is formulated in accordancewith routine procedures as a pharmaceutical composition adapted forintravenous administration to human beings. Typically, compositions forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where the composition is to be administered by infusion, it canbe dispensed with an infusion bottle containing sterile pharmaceuticalgrade water or saline. Where the composition is administered byinjection, an ampoule of sterile water for injection or saline can beprovided so that the ingredients may be mixed prior to administration.

The compositions of the invention can be formulated as neutral or saltforms. Pharmaceutically acceptable salts include those formed withanions such as those derived from hydrochloric, phosphoric, acetic,oxalic, tartaric acids, etc., and those formed with cations such asthose derived from sodium, potassium, ammonium, calcium, ferrichydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol,histidine, procaine, etc.

The amount of the composition of the invention which will be effectivein the treatment, inhibition and prevention of tumor growth associatedwith the antigen to which the antibody of the invention is specific canbe determined by standard clinical techniques. The presence of theantibody in the extra vascular space, can be assayed by standard skinwheal and flair responses, in response to intradermal administration ofpurified antigen (e.g. CA125). In addition, in vitro assays mayoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed in the formulation will also depend on theroute of administration, and the seriousness of the disease or disorder,and should be decided according to the judgment of the practitioner andeach patient's circumstances. Effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.

For the antibodies used in the invention, the dosage administered to apatient is typically 0.001 μg/kg to 1 mg/kg of the patient's bodyweight. Preferably, the dosage administered to a patient is between 0.01μg/kg and 0.1 mg/kg of the patient's body weight, more preferably 0.02μg/kg to 20 μg/kg of the patient's body weight. Lower dosages of theantibodies of the invention and less frequent administration may also bepossible.

For the chemotherapeutic agents used in the invention, the dosageadministered to a patient may be according to the ranges orconcentrations that have been optimized by their respectivemanufacturers.

For the immunostimulatory compound used in the invention, the dosageadministered to a patient may be according to the ranges orconcentrations that have been optimized by their respectivemanufacturers.

For the immune homeostatic checkpoint inhibitor used in the invention,the dosage administered to a patient may be according to the ranges orconcentrations that have been optimized by their respectivemanufacturers.

In embodiments, each disease is treated according to standard of caretreatment(s), where dosages of therapeutics administered to a patientmay be according to the ranges or concentrations that have beenoptimized by their respective manufacturers.

The pharmaceutical compositions of the present invention have in vitroand in vivo diagnostic and therapeutic utilities. For example, thesemolecules can be administered to cells in culture, e.g., in vitro or exvivo, or in a subject, e.g., in vivo, to treat cancer. As used herein,the term “subject” is intended to include human and non-human animals. Apreferred subject is a human patient with cancer. As used herein theterms “treat” “treating” and “treatment” of cancer includes: preventingthe appearance of tumor metastasis in a patient, inhibiting the onset ofcancer in a patient; eliminating or reducing a preexisting tumor burdenin a patient either with metastatic cancer or cancer localized to theorgan of origin; prolonging survival in a cancer patient; prolonging theremission period in a cancer patient following initial treatment withchemotherapy and/or surgery; and/or prolonging any period between cancerremission and cancer relapse in a patient.

When used for therapy for the treatment of cancer, the antibodies usedin the invention are administered to the patient in therapeuticallyeffective amounts (i.e. amounts needed to treat clinically apparenttumors, or prevent the appearance of clinically apparent tumor, eitherat the original site or a distant site, at some time point in thefuture). The antibodies used in the invention and the pharmaceuticalcompositions containing them will normally be administered parenterally,when possible, or at the target cell site, or intravenously.

According to yet another embodiment, the present invention alsoencompasses kits for use for inhibiting cancer tumor growth in a patientin need thereof. The kits may comprise a therapeutic monoclonal antibodyspecific for a tumor associated antigen, at least one immunostimulatorycompound, at least one immune homeostatic checkpoint inhibitor, andinstructions on how to use the kit.

The present invention will be more readily understood by referring tothe following examples which are given to illustrate the inventionrather than to limit its scope.

Example 1 Combining Front Line Chemotherapy and Immunotherapy

Now referring to FIG. 1, which is a schematic of the FrontlineChemoimmunotherapy Randomized Phase II trial according to an embodimentof the present invention.

Design:

Phase II Randomized trial (centers in US and Italy).

Patients:

Initial treatment of newly diagnosed optimally debulked stage III/IVOvarian cancer expressing CA125 (MUC16) at least 2× normal at baseline.

Treatment:

Standard of care (SOC) chemotherapy (6 cycles IV carboplatin-paclitaxel)(Control) vs SOC chemotherapy plus oregovomab immunotherapy (IT) (CIT)

Schedule:

In CIT group oregovomab is administered at cycles 1, 3, 5 in combinationwith the SOC chemotherapy, as well as at cycle 5 plus 12 weeks as asingle oregovomab immunotherapy immunization (without SOC chemotherapy).Initial Analysis post completion of treatment phase. Final Analysis post3 year follow up.

Endpoints:

Safety, Immune Response and Clinical Outcomes (TTCR, PFS and OS).

A total of 97 patients were enrolled in the intent to treat (ITT)population.

Oreqovomab MAb-B43.13

All patients in the CIT group enrolled in this study were to receivesingle IV doses of MAb-B43.13 containing 2 mg of the monoclonal antibodyconcurrent with conventional chemotherapy Cycles 1, 3 and 5.Subsequently all patients in the CIT group were to receive single IVdoses of MAb-B43.13 at Cycle 5+12 weeks in the post-chemotherapy phase(without concurrent chemotherapy).

The lyophilized contents of a vial of MAb-B43.13 were to be dissolved in2 mL of 0.9% Sodium Chloride Injection USP (or equivalent). The vialcontents were to be mixed by gentle swirling to avoid the formation offoam and then examined to ensure that the solution was free of foreignor particulate matter. The resulting solution was to be withdrawn fromthe vial with a suitable needle and syringe and added to 50 mL of 0.9%Sodium Chloride Injection USP (or equivalent) in a small (50 mL)infusion bag.

Each dose of MAb-B43.13 (containing 2 mg of MAb-B43.13 in 50 mL ofSodium Chloride Injection USP) was to be administered to the patient byslow (20 minutes) IV infusion in an appropriate treatment area. The doseof MAb-B43.13 was to be administered after paclitaxel but prior tocarboplatin.

Chemotherapy

Maximum body surface area (BSA) used for chemotherapy dose calculationswas to be determined per acceptable standard (e.g., Gynecologic OncologyGroup Chemotherapy Procedures Manual). Maximum creatinine clearance wasto be 120 mL/min for the purpose of this study.

Paclitaxel

Paclitaxel is supplied as a sterile solution concentrate, 6 mg/mL, in 5mL vials (30 mg/vial) or 17 mL vials (100 mg/vial) in polyoxyethylatedcastor oil (Cremophor EL) 50% and dehydrated alcohol, USP, 50%, was tobe used for this trial. The appropriate dose of paclitaxel was to bediluted in 500-1000 mL of 9% Sodium Chloride injection, USP or 5%Dextrose injection, USP (D5W). Paclitaxel was to be prepared in glass orpolyolefin containers due to leaching of diethylhexylphthalateplasticizer from polyvinyl chloride (PVC) bags and intravenous tubing bythe Cremophor vehicle in which paclitaxel is solubilized.

Paclitaxel, at a dose of 175 mg/m², was to be administered via aninfusion control device (pump) using non-PVC tubing and connectors, as a3-hour continuous IV infusion. In-line filtration was necessary foradministration of paclitaxel solutions. Due to the risk of immediatehypersensitivity reaction, paclitaxel should always be the first drug tobe infused during any combination.

Carboplatin

Carboplatin is supplied as a sterile lyophilized powder available insingle-dose vials containing 50 mg, 150 mg and 450 mg of carboplatin foradministration by IV infusion. Each vial contains equal parts by weightof carboplatin and mannitol.

Immediately prior to use, the contents of each vial was to bereconstituted with either sterile water for injection, USP, 5% dextrosein water, or 9% sodium chloride injection, USP, according to thefollowing schedule: 50 mg vial with 5 mL, 150 mg vial with 15 mL and 450mg vial with 45 mL, all producing a concentration of 10 mg/m L.

The dose of carboplatin was to be calculated to reach a target areaunder the curve (AUC) of concentration×time of 6 according to theCalvert formula using an estimated glomerular filtration rate (GFR) fromthe Jelliffe formula for creatinine clearance (CrCl).

Calvert Formula: Carboplatin dose (mg)=target AUC×(GFR+25)

For the purposes of this protocol, the GFR was considered to beequivalent to the CrCl. The creatinine clearance was to be estimated bythe method of Jelliffe using the following formula:

${CrCl} = {0.9 \times \frac{\left\lbrack {98 - \left( {0.8\left( {{Age} - 20} \right)} \right)} \right\rbrack}{{Serum}\mspace{14mu} {Creatinine}}}$

Where: CrCl=estimated creatinine clearance in mL/min; Age=patient's agein years; serum creatinine in mg/dL.

The initial dose of carboplatin was to be calculated using GFR. In theabsence of new renal obstruction or other renal toxicity (i.e., serumcreatinine>1.5×ULN), the dose of carboplatin was not to be recalculatedfor subsequent cycles, but was to be subject to dose modification forhematologic criteria and other events.

In patients with an abnormally low serum creatinine, due to reducedprotein intake and/or low muscle mass, the creatinine clearance (CrCl)was to be determined from a 24 hour urine collection, rather than aJelliffe formula.

Carboplatin was to be administered as a 30 minute IV infusion. Whenadministered in conjunction with other medications, carboplatin was tobe infused after the other agents.

TABLE 1 Demographics analysis of the ITT population ITT PopulationTreatment Treatment Arm 1 CIT Arm 2 SOC All (N = 47) (N = 50) (N = 97)Age (years) n 47 50 97 Mean (SD) 57.9 (11.4) 58.1 (10.4) 58.0 (10.8)Median 58.3 57.6 57.8 Mann-Whitney- 0.9971 Wilcoxon p-value Race African0 1 (2.0%) 1 (1.0%) White 47 (100%) 49 (98.0%) 96 (99.0%) Other 0 0 0Fisher p-value 1.0000 ECOG 0 39 (83.0) 46 (92.0%) 85 (87.6%) performancestatus ECOG 1 8 (17.0%) 4 (8.0%) 12 (12.4%) performance statusChi-square p-value 0.1775

TABLE 2 Ovarian Cancer Characteristics in the ITT ITT PopulationTreatment Treatment Arm 1 Arm 2 All (N = 47) (N = 50) (N = 97) Time fromn 47 49 96 diagnosis to randomization (years) n. missing 0 1 1 Median0.10 (0.01, 0.16) 0.11 (0.04, 0.36) 0.10 (0.01, 0.36) (Min, Max)Mann-Whitney- 0.4813 Wilcoxon p-value Tumor grade 0 0 (0.0%) 0 (0.0%) 0(0.0%) 1 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 6 (12.8%) 4 (8.0%) 10 (10.3%) 3 40(85.1%) 44 (88.0%) 84 (86.6%) 4 1 (2.1%) 0 (0.0%) 1 (1.0%) Unknown 0(0.0%) 2 (4.0%) 2 (2.1%) Fisher p-value 0.3234 Histology Mucinous 1(2.13%) 1 (2.0%) 2 (2.1%) Serous 42 (89.4%) 44 (88.0%) 86 (88.7%)Undifferentiated 0 (0.0%) 0 (0.0%) 0 (0.0%) Endometroid 4 (8.5%) 2(4.0%) 6 (6.2%) Clear Cell 0 (0.0%) 2 (4.0%) 2 (2.1%) Other 0 (0.0%) 1(2.%) 1 (1.0%) Fisher p-value 0.6041 Organ of origin Ovary 42 (89.4%) 43(86.0%) 85 (87.6%) Fallopian Tube 3 (6.4%) 2 (4.0%) 5 (5.2%) Peritoneum0 (0.0%) 4 (8.0%) 4 (4.1%) Ovary + 1 (2.1%) 1 (2.0%) 2 (2.1%) FallopianTube Missing 1 (2.1%) 0 (0.0%) 1 (1.0%) Fisher p-value 0.2488 FIGO stageIII 1 (2.1%) 2 (4.0%) 3 (3.1%) IIIA 5 (10.6%) 3 (6.0%) 8 (8.3%) IV 5(10.6%) 3 (6.0%) 8 (8.3%) IIIB 9 (19.2%) 3 (6.0%) 12 (12.4%) IIIC 27(57.5%) 39 (78.0%) 66 (68.0%) Missing 0 (0.0%) 0 (0.0%) 0 (0.00%) Fisherp-value 0.1508

TABLE 3 Summary of adverse events Safety Population Treatment TreatmentArm 1 CIT Arm 2 SOC All (N = 46) (N = 49) (N = 95) Patients with anyadverse event 38 (82.6%) 40 (81.6%) 78 (82.1%) Patients with any relatedadverse event 8 (17.4%) 9 (18.4%) 17 (17.9%) Patients with any seriousadverse event 10 (21.7%) 8 (16.3%) 18 (19.0%) Patients with any seriousrelated adverse event 0 (0.0%) 0 (0.0%) 0 (0.0%) Patients with any grade3-4 adverse event 24 (52.2%) 28 (57.1%) 52 (54.7%) Patients with anygrade 3-4 related adverse event 2 (4.4%) 4 (8.2%) 6 (6.3%) Patients withany adverse event leading to study 3 (6.5%) 1 (2.0%) 4 (4.2%) drugdiscontinuation (*) Patients with any adverse event leading death 1(2.2%) 1 (2.0%) 2 (2.1%) (*) Patients with permanent discontinuation

Oregovomab plus chemotherapy has similar adverse events profile tochemotherapy alone.

TABLE 4 Preliminary Clinical Data All patients Treatment Treatment Arm 1CIT Arm 2 SOC All Relapse Data (N = 47) (N = 50) (N = 97) Patients withYes 14 (29.8%) 29 (58.0%) 43 (44.3%) clinical relapse No 33 (70.2%) 21(42.0%) 54 (55.7%) Chi-square 0.0052 p-value

TABLE 5 Progression free survival (PFS) data maturation All patientsTreatment Arm 1 CIT Treatment Arm 2 SOC (N = 47) (N = 50) Censor summaryTotal: 47    49 Censors: 30 (63.8%) 17 (34.7%) Events: 17 (36.2%) 32(65.3%) Quartiles 75th percentile [—] 33.95 [18.74-] estimation 50thpercentile [21.30-] 15.39 [10.93-19.33] 25th percentile 19.18[9.98-28.59] 9.35 [7.12-11.11] Time to event Mean (SD) 24.76 (1.38)18.67 (1.73) estimation  0 month 100.00 [100.00-100.00] 100.00[100.00-100.00] Survival time  6 months 97.78 [85.25-99.68] 91.66[79.28-96.79] 12 months 84.13 [69.57-92.10] 57.55 [42.25-70.17] 18months 75.04 [59.47-85.33] 42.53 [28.30-56.04] 24 months 65.30[49.09-77.47] 33.25 [20.17-46.90] 30 months 61.46 [44.43-74.67] 33.25[20.17-46.90] 36 months 56.34 [37.89-71.23] 16.63 [1.80-44.87] 42 months56.34 [37.89-71.23] [—] 48 months [—] [—] Log-rank test Pr > Chi-Square0.0009

TABLE 6 Early Survival Data All patients Treatment Arm 1 CIT TreatmentArm 2 SOC Overall Survival ITT (N = 47) (N = 50) Censor summary Total:46(*)   49 Censors: 42 (91.3%) 33 (67.3%) Events: 4 (8.7%) 16 (32.7%)Quartiles 75th percentile [—] [38.34-] estimation 50th percentile [—]38.34 [26.45-] 25th percentile [30.91-] 21.18 [11.33-38.34] Time toevent Mean (SD) 29.32 (1.04) 29.89 (1.88) estimation  0 month 100.00[100.00-100.00] 100.00 [100.00-100.00] Survival time  6 months 97.73[84.94-99.68] 95.87 [84.49-98.95] 12 months 93.07 [80.04-97.71] 87.30[73.88-94.09] 18 months 93.07 [80.04-97.71] 78.39 [63.51-87.76] 24months 93.07 [80.04-97.71] 73.37 [57.73-83.98] 30 months 93.07[80.04-97.71] 66.67 [49.62-79.09] 36 months 87.60 [67.52-95.63] 57.14[33.49-75.11] 42 months 87.60 [67.52-95.63] 42.86 [15.14-68.37] 48months 87.60 [67.52-95.63] [—] Log-rank test Pr > Chi-Square 0.0025

While preferred embodiments have been described above and illustrated inthe accompanying drawings, it will be evident to those skilled in theart that modifications may be made without departing from thisdisclosure. Such modifications are considered as possible variantscomprised in the scope of the disclosure.

1.-19. (canceled)
 20. A method for improving likelihood of survival in astage III-IV ovarian cancer patient, the method comprising: (a)administering to a stage III-IV ovarian cancer patient 6 cycles ofchemotherapy, wherein in each cycle the patient is administered aplatinum-based chemotherapy and a taxane on the same day; (b)administering to the patient monoclonal antibody mAb-B43.13 concurrentlyduring cycles 1, 3, and 5 of the 6 cycles of chemotherapy; and (c)administering to the patient in a final dose of monoclonal antibodymAb-B43.13 without concurrent chemotherapy about 10 to about 14 weeksafter cycle 5 of the 6 cycles of chemotherapy, thereby increasing thepatient's likelihood of survival in comparison with a control patientwho has been diagnosed with stage III-IV ovarian cancer and has receivedtreatment consisting of 6 cycles of chemotherapy consisting of saidplatinum-based chemotherapy and said taxane administration, wherein themethod comprises no other treatment step in which mAb-B43.13, saidplatinum-based chemotherapy, or said taxane is administered to thepatient, and wherein in step (b) said taxane, said platinum-basedchemotherapy, and mAb-B43.13 are administered in this order on the sameday.
 21. The method of claim 20, wherein time interval between every twoconsecutive cycles of the 6 cycles of chemotherapy is 1 week, 2 weeks,or 1 month.
 22. The method of claim 20, wherein time interval betweenevery two consecutive cycles of the 6 cycles of chemotherapy is 3 weeks.23. The method of claim 20, wherein step (c) is performed about 12 weeksafter cycle 5 of the 6 cycles of chemotherapy.
 24. The method of claim20, wherein each of mAb-B43.13, carboplatin, and paclitaxel isintravenously administered.
 25. The method of claim 20, wherein 2 mg ofmAb-B43.13 is administered in a volume of 50 ml by a 20-minute infusion.26. The method of claim 20, wherein said platinum-based chemotherapycomprises cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatintetranitrate, phenanthriplatin, picoplatin, satraplatin, andcombinations thereof.
 27. The method of claim 26, wherein saidplatinum-based chemotherapy is carboplatin.
 28. The method of claim 20,wherein said taxane is paclitaxel, docetaxel, and a combination thereof.29. The method of claim 28, wherein said taxane is paclitaxel.
 30. Themethod of claim 20, wherein step (c) of administering to the patient ina final dose of monoclonal antibody mAb-B43.13 without concurrentchemotherapy is at about 12 weeks after cycle 5 of the 6 cycles ofchemotherapy.
 31. The method of claim 20, wherein step (c) comprises nofollow-up therapy.